The NIMH Collaborative Program on the Psychobiology of Depression ("Collaborative Depression Study") is studying the nosology, clinical course and followup, familial and genetic, and psychosocial factors affective disorders. The Collaborative Depression Study samples include 955 probands (both inpatients and outpatients), 2,252 first-degree relatives and 404 matched controls, and 337 spouses of probands. At present, the probands are being followed annually and a six-year re-evaluation of relatives, spouses, and controls is nearly completed. This application proposes (a) completion of the six-year re- evaluation of relatives, spouses, and controls; (b) completion of the semi-annual assessment of 250 high-risk relatives; (c) continuation of data analysis of proband and relatives data; and (d) continued yearly followup of the probands. Reevaluation of relatives, spouses, and controls allows prospective assessment of individuals as a function of familial loading, sociodemographic variables, and personality. This sample included a substantial number of individuals with no history of psychiatric disorder prior to the first evaluation. The six-year re-evaluation therefore allows an opportunity for true prospective disorder. For those subjects with a history of affective disorder prior to the first evaluation, this sample provides an excellent opportunity to study the predictors of future episodes and the clinical course of a milder form of depression. Finally, subjects with non- affective illness will be used to study predictors of secondary depression and its relationship to untreated alcoholism and anxiety disorders. Independent assessments of lifetime psychiatric history at two points in time are being made. This procedure allows quantification and improvement of diagnostic stability. New methods that are in the process of being developed will measure sensitivity and specificity of diagnosis, diagnostic validity, familial transmission and secular trends. Two hundred and fifty high-risk subjects from families are being re-evaluated semi-annually for three years; one-quarter are expected to experience major depression. A final, blind reassessment of the preceding three years will permit a measure of validity for items assessed in the follow-up of the entire sample of relatives. Furthermore, mild and untreated episodes will be followed in the same way as the severe episodes in probands permitting more general interpretation of our findings.